Potent 1,2,4-Triazino[5,6 b]indole-3-thioether Inhibitors of the Kanamycin Resistance Enzyme Eis from Mycobacterium tuberculosis

Huy X. Ngo, Keith D. Green, Chathurada S. Gajadeera, Melisa J. Willby, Selina Y.L. Holbrook, Caixia Hou, Atefeh Garzan, Abdelrahman S. Mayhoub, James E. Posey, Oleg V. Tsodikov, Sylvie Garneau-Tsodikova

Research output: Contribution to journalArticlepeer-review

21 Scopus citations

Abstract

A common cause of resistance to kanamycin (KAN) in tuberculosis is overexpression of the enhanced intracellular survival (Eis) protein. Eis is an acetyltransferase that multiacetylates KAN and other aminoglycosides, rendering them unable to bind the bacterial ribosome. By high-throughput screening, a series of substituted 1,2,4-triazino[5,6b]indole-3-thioether molecules were identified as effective Eis inhibitors. Herein, we purchased 17 and synthesized 22 new compounds, evaluated their potency, and characterized their steady-state kinetics. Four inhibitors were found not only to inhibit Eis in vitro, but also to act as adjuvants of KAN and partially restore KAN sensitivity in a Mycobacterium tuberculosis KAN-resistant strain in which Eis is upregulated. A crystal structure of Eis in complex with a potent inhibitor and CoA shows that the inhibitors bind in the aminoglycoside binding site snugly inserted into a hydrophobic cavity. These inhibitors will undergo preclinical development as novel KAN adjuvant therapies to treat KAN-resistant tuberculosis.

Original languageEnglish
Pages (from-to)1030-1040
Number of pages11
JournalACS Infectious Diseases
Volume4
Issue number6
DOIs
StatePublished - Jun 8 2018

Bibliographical note

Publisher Copyright:
© 2018 American Chemical Society.

Keywords

  • aminoglycoside resistance
  • antitubercular agent
  • combination therapy
  • high-throughput screen
  • structure-activity relationship (SAR)

ASJC Scopus subject areas

  • Infectious Diseases

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